1. Field of the Disclosure
The present disclosure provides methods for the treatment of autoimmune diseases such as systemic lupus erythematosus, scleroderma, lupus nephritis, and myositis with fixed doses of anti-interferon receptor antibodies.
2. Background Art
Type I interferons (IFNs) are a family of cytokines including 14 IFN-α subtypes, IFN-β, -ω, and −κ, all of which are involved in antiviral or antitumor function. A potential role for type I IFNs in the disease pathogenesis of several autoimmune disorders including systemic sclerosis (SSc, scleroderma), systemic lupus erythematous (SLE), primary Sjögren's, rheumatoid arthritis, as well as myositis.
SLE is a chronic rheumatic disease characterized by autoreactive antibodies targeting a variety of self-antigens resulting in inflammation, tissue and organ damage. The role of type I IFNs has been implicated in the development of SLE. SSc is a rheumatic disease of the connective tissue, affecting multiple systems including skin, muscle, and internal organs. Like SLE, increased type I IFN activity plays a role in the pathogenesis of SSc, as confirmed by the over-expression of type I IFN-inducible genes and the enrichment of plasmacytoid dendritic cells in skin and/or blood of SSc patients (Fleming et al., PLoS One 3:e1452 (2008); Coelho et al., Arch. Dermatol. Res. 299:259-262 (2007); Tan et al., Rheumatology (Oxford) 45:694-702 (2006); Duan et al., Arthritis Rheum. 58:1465-1474 (2008)). These observations along with other data including animal model studies have suggested type I IFN signaling as a viable therapeutic target in both SLE and SSc (Tan et al., Rheumatology (Oxford) 45:694-702 (2006); 28. Crow, Rheum. Dis. Clin. North Am. 36:173-186 (2010); York et al., Arthritis Rheum. 56:1010-1020 (2007)).
Type I IFNs in serum or plasma are not easily measured. On the other hand, type I IFN inducible genes can be conveniently measured improved sensitivity and specificity (Bengtsson et al., Lupus 9:664-671 (2000); Dall'era et al., Ann. Rheum. Dis. 64:1692-1697 (2005); Kirou et al., Arthritis Rheum. 50:3958-3967 (2004)). Several well defined type I IFN signatures have been used to correlate type I IFN activity with SLE or SSc disease pathogenesis (Eloranta et al., Ann. Rheum. Dis. 69:1396-1402 (2010)), disease activity (Bilgic et al., Arthritis Rheum. 60:3436-3446 (2009)), as well as assessing the drug-target interaction (i.e., pharmacodynamics, PD) of an anti-IFN-α therapy in SLE (Yao et al., Arthritis Rheum. 60:1785-1796 (2009); Yao et al., Hum. Genomics Proteomics 2009:374312 (2009); Yao et al., Arthritis Res. Ther. 12 (Suppl 1):S6 (2010)). The development of a type I IFN signature to identify subpopulations showing both activation and concordance of the type I IFN pathway between the peripheral blood and disease-affected tissues in both SLE and SSc (Higgs et al., Ann. Rheum. Dis. 70:2029-2036 (2011)) has demonstrated the potential utility of using a type I IFN signature as a PD marker in both diseases.
The clinical development of a new drug is a lengthy and costly process with low odds of success, and contrary to common impression, the clinical development of biotherapeutics, especially monoclonal antibodies, is not quicker or cheaper than small molecule drugs (DiMasi et al., Clin. Pharmacol. Ther. 87:272-277 (2010)). The early clinical development of biotherapeutics, in particular Phase 1 is much lengthier than for small molecules. Absent definitive efficacy signal from early phase studies in patients, a sensitive, disease-relevant and robust biomarker can greatly aid the interpretation of clinical results.
Type I IFN-mediated diseases such as SLE present diverse disease manifestations and highly variable disease progression, flares and remissions. Due to this heterogeneity, it is crucial to identify patients with similar pathway activation parameters to designate the most appropriate therapies for the different patient subsets. To expedite the clinical development and improve the odds of success, a relevant, sensitive and robust set of PD markers that can be easily tracked or monitored in patients is of great value for dose finding at the early clinical development stage. Methods of applying this set of PD markers would be highly valuable tools to account for differences in target expression and pathway activation in different diseases, and to facilitate bridging between clinical trials in different indications.